Delivery of muscle relaxants through an inhalation route

ABSTRACT

The present invention relates to the delivery of muscle relaxants through an inhalation route. Specifically, it relates to aerosols containing muscle relaxants that are used in inhalation therapy. In a method aspect of the present invention, a muscle relaxant is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of a muscle relaxant, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% muscle relaxant degradation products. In a kit aspect of the present invention, a kit for delivering a muscle relaxant through an inhalation route is provided which comprises: a) a coating of a muscle relaxant and b) a device for dispensing said coating a muscle relaxant as a condensation aerosol.

This application is a continuation of U.S. patent application Ser. No.10/150,267, entitled “Delivery of Muscle Relaxants Through an InhalationRoute,” filed May 15, 2002, now U.S. Pat. No. 6,797,259 Rabinowitz andZaffaroni, which claims priority to U.S. provisional application Ser.No. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24,2001, Rabinowitz and Zaffaroni, the entire disclosure of which is herebyincorporated by reference. This application further claims priority toU.S. provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entiredisclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of muscle relaxantsthrough an inhalation route. Specifically, it relates to aerosolscontaining muscle relaxants that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of compositions currently marketed as musclerelaxants. The compositions contain at least one active ingredient thatprovides for observed therapeutic effects. Among the active ingredientsgiven in muscle relaxant compositions are quinine, chlorzoxazone,carisprodol and cyclobenzaprine.

It is desirable to provide a new route of administration for musclerelaxants that rapidly produces peak plasma concentrations of thecompound. The provision of such a route is an object of the presentinvention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of muscle relaxantsthrough an inhalation route. Specifically, it relates to aerosolscontaining muscle relaxants that are used in inhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of a muscle relaxant.Preferably, the particles comprise at least 10 percent by weight of amuscle relaxant. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or99.97 percent by weight of a muscle relaxant.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofmuscle relaxant degradation products. Preferably, the particles compriseless than 5 percent by weight of muscle relaxant degradation products.More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or0.03 percent by weight of muscle relaxant degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

Typically, the aerosol is formed by heating a composition containing amuscle relaxant to form a vapor and subsequently allowing the vapor tocondense into an aerosol.

In another composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of quinine,chlorzoxazone, carisprodol or cyclobenzaprine. Preferably, the particlescomprise at least 10 percent by weight of quinine, chlorzoxazone,carisprodol or cyclobenzaprine. More preferably, the particles compriseat least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent or 99.97 percent by weight of quinine, chlorzoxazone,carisprodol or cyclobenzaprine.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofquinine, chlorzoxazone, carisprodol or cyclobenzaprine degradationproducts. Preferably, the particles comprise less than 5 percent byweight of quinine, chlorzoxazone, carisprodol or cyclobenzaprinedegradation products. More preferably, the particles comprise less than2.5, 1, 0.5, 0.1 or 0.03 percent by weight of quinine, chlorzoxazone,carisprodol or cyclobenzaprine degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, where the aerosol comprises quinine, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 500 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 20 mg/L and 400 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 50 mg/L and 300 mg/L.

Typically, where the aerosol comprises chlorzoxazone, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 400 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 20 mg/L and 300 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 50 mg/L and 200 mg/L.

Typically, where the aerosol comprises carisprodol, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 500 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 20 mg/L and 400 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 50 mg/L and 200 mg/L.

Typically, where the aerosol comprises cyclobenzaprine, the aerosol hasan inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 2 mg/L and 15 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 4 mg/L and 10 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s). In certain embodiments the particles have an MMAD of fromabout 0.2 to about 3 microns.

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

Typically, the aerosol is formed by heating a composition containingquinine, chlorzoxazone, carisprodol or cyclobenzaprine to form a vaporand subsequently allowing the vapor to condense into an aerosol.

In a method aspect of the present invention, a muscle relaxant isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of a muscle relaxant, to form a vapor; and, b)allowing the vapor to cool, thereby forming a condensation aerosolcomprising particles, which is inhaled by the mammal. Preferably, thecomposition that is heated comprises at least 10 percent by weight of amuscle relaxant. More preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of a muscle relaxant.

Typically, the particles comprise at least 5 percent by weight of amuscle relaxant. Preferably, the particles comprise at least 10 percentby weight of a muscle relaxant. More preferably, the particles compriseat least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of a musclerelaxant.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofmuscle relaxant degradation products. Preferably, the particles compriseless than 5 percent by weight of muscle relaxant degradation products.More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percentby weight of muscle relaxant degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of a muscle relaxant in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

In another method aspect of the present invention, one of quinine,chlorzoxazone, carisprodol or cyclobenzaprine is delivered to a mammalthrough an inhalation route. The method comprises: a) heating acomposition, wherein the composition comprises at least 5 percent byweight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine, toform a vapor; and, b) allowing the vapor to cool, thereby forming acondensation aerosol comprising particles, which is inhaled by themammal. Preferably, the composition that is heated comprises at least 10percent by weight of quinine, chlorzoxazone, carisprodol orcyclobenzaprine. More preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of quinine, chlorzoxazone,carisprodol or cyclobenzaprine.

Typically, the particles comprise at least 5 percent by weight ofquinine, chlorzoxazone, carisprodol or cyclobenzaprine. Preferably, theparticles comprise at least 10 percent by weight of quinine,chlorzoxazone, carisprodol or cyclobenzaprine. More preferably, theparticles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofquinine, chlorzoxazone, carisprodol or cyclobenzaprine degradationproducts. Preferably, the particles comprise less than 5 percent byweight of quinine, chlorzoxazone, carisprodol or cyclobenzaprinedegradation products. More preferably, the particles comprise 2.5, 1,0.5, 0.1 or 0.03 percent by weight of quinine, chlorzoxazone,carisprodol or cyclobenzaprine degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

Typically, where the aerosol comprises quinine, the delivered aerosolhas an inhalable aerosol drug mass density of between 10 mg/L and 500mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 20 mg/L and 400 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 50 mg/L and 300 mg/L.

Typically, where the aerosol comprises chlorzoxazone, the deliveredaerosol has an inhalable aerosol drug mass density of between 10 mg/Land 400 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 20 mg/L and 300 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 50 mg/L and 200mg/L.

Typically, where the aerosol comprises carisprodol, the deliveredaerosol has an inhalable aerosol drug mass density of between 10 mg/Land 500 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 20 mg/L and 400 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 50 mg/L and 300mg/L.

Typically, where the aerosol comprises cyclobenzaprine, the deliveredaerosol has an inhalable aerosol drug mass density of between 1 mg/L and20 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 2 mg/L and 15 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 4 mg/L and 10 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises quinine, between 50mg and 500 mg of quinine are delivered to the mammal in a singleinspiration. Preferably, between 100 mg and 450 mg of quinine aredelivered to the mammal in a single inspiration. More preferably,between 100 mg and 400 mg of quinine are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises chlorzoxazone,between 50 mg and 400 mg of chlorzoxazone are delivered to the mammal ina single inspiration. Preferably, between 100 mg and 350 mg ofchlorzoxazone are delivered to the mammal in a single inspiration. Morepreferably, between 100 mg and 300 mg of chlorzoxazone are delivered ina single inspiration.

Typically, where the condensation aerosol comprises carisprodol, between70 mg and 500 mg of carisprodol are delivered to the mammal in a singleinspiration. Preferably, between 150 mg and 450 mg of carisprodol aredelivered to the mammal in a single inspiration. More preferably,between 150 mg and 400 mg of carisprodol are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises cyclobenzaprine,between 2 mg and 25 mg of cyclobenzaprine are delivered to the mammal ina single inspiration. Preferably, between 5 mg and 20 mg ofcyclobenzaprine are delivered to the mammal in a single inspiration.More preferably, between 5 mg and 15 mg of cyclobenzaprine are deliveredto the mammal in a single inspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of quinine, chlorzoxazone, carisprodol or cyclobenzaprinein the mammal in less than 1 h. Preferably, the peak plasmaconcentration is reached in less than 0.5 h. More preferably, the peakplasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01h, or 0.005 h (arterial measurement).

Typically, the delivered condensation aerosol is used to treatmusculoskeletal pain.

In a kit aspect of the present invention, a kit for delivering a musclerelaxant through an inhalation route to a mammal is provided whichcomprises: a) a composition comprising at least 5 percent by weight of amuscle relaxant; and, b) a device that forms a muscle relaxant aerosolfrom the composition, for inhalation by the mammal. Preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of a muscle relaxant.

Typically, the device contained in the kit comprises: a) an element forheating the muscle relaxant composition to form a vapor; b) an elementallowing the vapor to cool to form an aerosol; and, c) an elementpermitting the mammal to inhale the aerosol.

In another kit aspect of the present invention, a kit for deliveringquinine, chlorzoxazone, carisprodol or cyclobenzaprine through aninhalation route to a mammal is provided which comprises: a) acomposition comprising at least 5 percent by weight of quinine,chlorzoxazone, carisprodol or cyclobenzaprine; and, b) a device thatforms an quinine, chlorzoxazone, carisprodol or cyclobenzaprine aerosolfrom the composition, for inhalation by the mammal. Preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

Typically, the device contained in the kit comprises: a) an element forheating the quinine, chlorzoxazone, carisprodol or cyclobenzaprinecomposition to form a vapor; b) an element allowing the vapor to cool toform an aerosol; and, c) an element permitting the mammal to inhale theaerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliver musclerelaxant aerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of muscle relaxant perunit volume of aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Carisprodol” refers toN-isopropyl-2-methyl-2-propyl-1,3-propanediol-dicarbamate.

“Carisprodol degradation product” refers to a compound resulting from achemical modification of carisprodol. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Chlorzoxazone” refers to 5-chloro-2-hydroxy-benzoxazole.

“Chlorzoxazone degradation product” refers to a compound resulting froma chemical modification of chlorzoxazone. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Cyclobenzaprine” refers to3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine.

“Cyclobenzaprine degradation product” refers to a compound resultingfrom a chemical modification of cyclobenzaprine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Muscle relaxant degradation product” refers to a compound resultingfrom a chemical modification of a muscle relaxant. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Quinine” refers to6-methoxy-α-(5-vinyl-2-quinuclidinyl)-4-quinoline-methanol.

“Quinine degradation product” refers to a compound resulting from achemical modification of quinine. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of muscle relaxantproduced by an inhalation device per unit time.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of Muscle Relaxant Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising a muscle relaxant to form a vapor, followed by cooling of thevapor such that it condenses to provide a muscle relaxant comprisingaerosol (condensation aerosol). The composition is heated in one of fourforms: as pure active compound (e.g., pure quinine, chlorzoxazone,carisprodol or cyclobenzaprine); as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

Salt forms of muscle relaxants (e.g., quinine, chlorzoxazone,carisprodol or cyclobenzaprine) are either commercially available or areobtained from the corresponding free base using well known methods inthe art. A variety of pharmaceutically acceptable salts are suitable foraerosolization. Such salts include, without limitation, the following:hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formicacid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with the muscle relaxant. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yams and felts are available from American Kynol, Inc., New York,N.Y. Chromatography resins such as octadecycl silane chemically bondedto porous silica are exemplary coated variants of silica.

The heating of the muscle relaxant compositions is performed using anysuitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic solvation, hydration of pyrophoric materials and oxidation ofcombustible materials.

Delivery of Muscle Relaxant Containing Aerosols

Muscle relaxant containing aerosols of the present invention aredelivered to a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating a muscle relaxant containing composition to form a vapor; anelement allowing the vapor to cool, thereby providing a condensationaerosol; and, an element permitting the mammal to inhale the aerosol.Various suitable heating methods are described above. The element thatallows cooling is, in it simplest form, an inert passageway linking theheating means to the inhalation means. The element permitting inhalationis an aerosol exit portal that forms a connection between the coolingelement and the mammal's respiratory system.

One device used to deliver the muscle relaxant containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a proximal end102 and a distal end 104, a heating module 106, a power source 108, anda mouthpiece 110. A muscle relaxant composition is deposited on asurface 112 of heating module 106. Upon activation of a user activatedswitch 114, power source 108 initiates heating of heating module 106(e.g, through ignition of combustible fuel or passage of current througha resistive heating element). The muscle relaxant compositionvolatilizes due to the heating of heating module 106 and condenses toform a condensation aerosol prior to reaching the mouthpiece 110 at theproximal end of the device 102. Air flow traveling from the devicedistal end 104 to the mouthpiece 110 carries the condensation aerosol tothe mouthpiece 110, where it is inhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of muscle relaxant containing aerosols. For instance, thedevice may include any component known in the art to control the timingof drug aerosolization relative to inhalation (e.g., breath-actuation),to provide feedback to patients on the rate and/or volume of inhalation,to prevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

Dosage of Muscle Relaxant Containing Aerosols

The dosage amount of muscle relaxants in aerosol form is generally nogreater than twice the standard dose of the drug give orally. Forinstance, quinine, chlorzoxazone, carisprodol and cyclobenzaprine aregiven at strengths of 260 mg to 325 mg, 250 mg, 350 mg, and 10 mgrespectively for the treatment of musculoskeletal pain. As aerosols, 50mg to 500 mg of quinine, 50 mg to 400 mg of chlorzoxazone, 70 mg to 500mg of carisprodol, and 2 mg to 25 mg of quinine are generally providedper inspiration for the same indication. A typical dosage of a musclerelaxant aerosol is either administered as a single inhalation or as aseries of inhalations taken within an hour or less (dosage equals sum ofinhaled amounts). Where the drug is administered as a series ofinhalations, a different amount may be delivered in each inhalation.

One can determine the appropriate dose of muscle relaxant containingaerosols to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug in an animalafter its exposure to the aerosol. Mammals such as dogs or primates aretypically used in such studies, since their respiratory systems aresimilar to that of a human. Initial dose levels for testing in humans isgenerally less than or equal to the dose in the mammal model thatresulted in plasma drug levels associated with a therapeutic effect inhumans. Dose escalation in humans is then performed, until either anoptimal therapeutic response is obtained or a dose-limiting toxicity isencountered.

Analysis of Muscle Relaxant Containing Aerosols

Purity of a muscle relaxant containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271–1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158–162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of musclerelaxant degradation products.

Particle size distribution of a muscle relaxant containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringa muscle relaxant containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure muscle relaxant, the amount of drug collected in thechamber is measured as described above. The rate of drug aerosolformation is equal to the amount of muscle relaxant collected in thechamber divided by the duration of the collection time. Where the musclerelaxant containing aerosol comprises a pharmaceutically acceptableexcipient, multiplying the rate of aerosol formation by the percentageof muscle relaxant in the aerosol provides the rate of drug aerosolformation.

Utility of Muscle Relaxant Containing Aerosols

The muscle relaxant containing aerosols of the present invention aretypically used for the treatment musculoskeletal pain or restless legsyndrome.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Quinine sulfate and cyclobenzaprine hydrochloride are commerciallyavailable from Sigma (www.sigma-aldrich.com). Carisprodol is availablein tablet form (SOMA®), from which it is isolated using standardprocedures known to one of ordinary skill in the art. Chlorzoxazone isavailable in caplet form (PARAFON FORTE® DSC), from which it is isolatedusing standard procedures known to one of ordinary skill in the art.

EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt

Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved indeionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds from Halogen Bulb

A solution of drug in approximately 120 μL dichloromethane is coated ona 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). Thedichloromethane is allowed to evaporate. The coated foil is wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which is inserted into a glass tube sealed at one end with arubber stopper. Running 60 V of alternating current (driven by linepower controlled by a variac) through the bulb for 6 s (quinine) or 90 Vfor 5 s (chlorzoxazone, carisprodol and cyclobenzaprine) affords thermalvapor (including aerosol), which is collected on the glass tube walls.Reverse-phase HPLC analysis with detection by absorption of 225 nm lightis used to determine the purity of the aerosol. (When desired, thesystem is flushed through with argon prior to volatilization.)

Quinine, chlorzoxazone, and cyclobenzaprine aerosol were obtained in100% (0.97 mg), 99.71% (1.55 mg), and 99.03% purity (6.33 mg)respectively using this procedure.

1. A method of treating musculoskeletal pain or restless leg syndrome ina patient comprising administering a therapeutic amount of a drugcondensation aerosol to the patient by inhalation, wherein the drug isselected from the group consisting of quinine, chlorzoxazone,carisprodol and cyclobenzaprine, and wherein the condensation aerosol isformed by heating a thin layer containing the drug, on a solid support,to produce a vapor of the drug, and condensing the vapor to form acondensation aerosol characterized by less than 10% drug degradationproducts by weight, and an MMAD of less than 5 microns.
 2. The methodaccording to claim 1, wherein the condensation aerosol is characterizedby an MMAD of less than 3 microns.
 3. The method according to claim 1,wherein peak plasma drug concentration is reached in less than 0.1hours.
 4. The method according to claim 1, wherein the condensationaerosol is formed at a rate greater than 0.5 mg/second.
 5. The methodaccording to claim 1, wherein at least 50% by weight of the condensationaerosol is amorphous in form.
 6. The method according to claim 1,wherein the therapeutic amount of a drug condensation aerosol comprisesbetween 50 mg and 500 mg of quinine delivered in a single inspiration.7. The method according to claim 1, wherein the therapeutic amount of adrug condensation aerosol comprises between 50 mg and 400 mg ofchlorzoxazone delivered in a single inspiration.
 8. The method accordingto claim 1, wherein the therapeutic amount of a drug condensationaerosol comprises between 70 mg and 500 mg of carisprodol delivered in asingle inspiration.
 9. The method according to claim 1, wherein thetherapeutic amount of a drug condensation aerosol comprises between 2 mgand 25 mg of cyclobenzaprine delivered in a single inspiration.
 10. Amethod of administering a drug condensation aerosol to a patient,comprising administering the drug condensation aerosol to the patient byinhalation, wherein the drug is selected from the group consisting ofquinine, chlorzoxazone, carisprodol and cyclobenzaprine, and wherein thedrug condensation aerosol is formed by heating a thin layer containingthe drug, on a solid support, to produce a vapor of the drug, andcondensing the vapor to form a condensation aerosol characterized byless than 10% durg degradation products by weight, and an MMAD of lessthan 5 microns.
 11. A kit for delivering a drug condensation aerosolcomprising: a. a thin layer containing the drug, on a solid support,wherein the drug is selected from the group consisting of quinine,chlorzoxazone, carisprodol and cyclobenzaprine, and b. a device forproviding the condensation aerosol, wherein the condensation aerosol isformed by heating the thin layer to produce a vapor of the drug, andcondensing the vapor to form a condensation aerosol characterized byless than 10% drug degradation products by weight, and an MMAD of lessthan 5 microns.
 12. The kit according to claim 11, wherein the devicecomprises a. a flow through enclosure containing the solid support, b. apower source that can be activated to heat the solid support, and c. atleast one portal through which air can be drawn by inhalation, whereinactivation of the power source is effective to produce a vapor of thedrug, and drawing air through the enclosure is effective to condense thevapor to form the condensation aerosol.
 13. The kit according to claim12, wherein the heat for heating the solid support is generated by anexothermic chemical reaction.
 14. The kit according to claim 13, whereinthe exothermic chemical reaction is oxidation of combustible materials.15. The kit according to claim 12, wherein the heat for heating thesolid support is generated by passage of current through an electricalresistance element.
 16. The kit according to claim 12, wherein the solidsupport has a surface area dimensioned to accommodate a therapeutic doseof the drug.
 17. The kit according to claim 11, wherein peak plasma drugconcentration is reached in less than 0.1 hours.
 18. The kit accordingto claim 11, further including instructions for use.
 19. The methodaccording to claim 1, wherein the condensation aerosol is characterizedby an MMAD of 0.1 to 5 microns.
 20. The method according to claim 2,wherein the condensation aerosol is characterized by an MMAD of about0.2 to about 3 microns.
 21. The method according to claim 10, whereinthe drug is quinine.
 22. The method according to claim 10, wherein thedrug is chlorzoxazone.
 23. The method according to claim 10, wherein thedrug is carisprodol.
 24. The method according to claim 10, wherein thedrug is cyclobenzaprine.
 25. The kit according to claim 11, wherein thecondensation aerosol is characterized by an MMAD of less than 3 microns.26. The kit according to claim 11 wherein the condensation aerosol ischaracterized by an MMAD of 0.1 to 5 microns.
 27. The kit according toclaim 11, wherein the condensation aerosol is characterized by an MMADof about 0.2 to about 3 microns.
 28. The kit according to claim 11,wherein the drug is quinine.
 29. The kit according to claim 11, whereinthe drug is chlorzoxazone.
 30. The kit according to claim 11, whereinthe drug is carisprodol.
 31. The kit according to claim 11, wherein thedrug is cyclobenzaprine.
 32. The kit according to claim 12, wherein thesolid support has a surface to mass ratio of greater than 1 cm² pergram.
 33. The kit according to claim 12, wherein the solid support has asurface to volume ratio of greater than 100 per meter.
 34. The kitaccording to claim 12, wherein the solid support is a metal foil. 35.The kit according to claim 34, wherein the metal foil has a thickness ofless than 0.25 mm.